Stereotactic ablative radiotherapy versus conventional fractionated radiotherapy for clinical early‐stage non‐small‐cell lung cancer: a population‐based study

Abstract Introduction The use of stereotactic ablative radiotherapy (SABR) over conventional fractionated radiotherapy (CFRT) for early‐stage non‐small‐cell lung cancer (NSCLC) has been advocated, but is also debated in the literature. Methods In this retrospective cohort study, we adopted a target trial emulation framework to identify eligible patients diagnosed between 2011 and 2021 using the Taiwan Cancer Registry. In the primary analysis, the overall survival (OS) was the primary endpoint, whereas incidences of lung cancer mortality and radiation pulmonary toxicity were the secondary endpoints. Extensive supplementary analyses were also conducted. Results We included 351 patients in the primary analysis and found that the OS was not significantly different between the SABR (n = 290) and CFRT (n = 61) groups. The propensity score weighting adjusted hazard ratio of death was 0.75 (95% confidence interval 0.53–1.07, p = 0.118). The secondary endpoints and supplementary analyses showed no significant differences. Conclusions The OS of patients with early‐stage NSCLC treated with SABR was not significantly different from that of patients treated with CFRT alone. The results of the relevant ongoing clinical trials are eagerly awaited.


INTRODUCTION
Lung cancer is a leading cause of cancer mortality around the world, including in Taiwan. 1,2Most cases include nonsmall-cell lung cancer (NSCLC), 1,2 where surgery is the treatment of choice for early-stage disease. 1,3However, radiotherapy is indicated for cases not suitable for surgery, wherein stereotactic ablative radiotherapy (SABR) or stereotactic body radiotherapy (SBRT) is preferred over conventional fractionated radiotherapy (CFRT). 1,4[6] However, a systematic review published in 2023 challenged the superiority of SABR. 7Based on two published randomized controlled trials (RCTs), 8,9 it stated that "Despite widespread adoption and extensive single-arm prospective and retrospective studies suggesting its benefit, this systematic review and meta-analysis of randomized trials fail to confirm improvements in local control, overall survival (OS), and toxicity profile of SABR over CFRT in early NSCLC."These findings are consistent with the primary analyses in our previous retrospective study published in 2017. 10onsidering the aforementioned debate comparing the efficacy of SABR to that of CFRT in early-stage NSCLC, and the scarcity of retrospective studies from Asia, 11 we conducted this updated retrospective cohort study utilizing the Taiwan Cancer Registry (TCR) and the target trial emulation framework. 12,13This study includes more recent patients and an extended follow-up period.

Data source
The Health and Welfare Data Science Center (HWDC) database, with personal identifiers removed, includes complete information regarding the TCR, death registration, and reimbursement data for the entire Taiwanese population provided by the Bureau of National Health Insurance.The TCR is one of the highest quality cancer registries worldwide. 14This study was approved by the Central Regional Research Ethics Committee of China Medical University, Taichung, Taiwan (CRREC-108-080 [CR-4]).

Study design, population, and intervention
In this retrospective cohort study, we adopted the target trial emulation framework. 12,13,15Our target trial design was modified from available RCTs [7][8][9] and the National Comprehensive Cancer Network guidelines 4 (see Table 1 for details of the study design).
We identified patients with NSCLC who met the following inclusion criteria: tumor staging according to the American Joint Committee on Cancer (AJCC) (7th edition, T1-2aN0M0 or 8th edition, T1-2N0M0, with tumor size ≤5 cm in both editions), age ≥18 years, 16,17 diagnosed between 2011 and 2021, and received curative radiotherapy without surgery.Patients were further classified as the SABR group (fractional [Fx] dose ≥6 Gy/Fx, total fractions ≤10 Fx, and total BED (10) ≥87.5) or the CFRT group (fractional dose within 2 À ≤2.5 Gy/Fx and total BED (10) within 62.5-84).The choice of these cutoff doses/fractionations was based on guidelines and pivotal trials. 4,9he primary outcome of interest was OS.Incidences of lung cancer mortality (ILCM) and radiation pulmonary toxicity were considered secondary outcomes.These outcomes were evaluated through linkages with the TCR, death registry, or reimbursement records.The first radiotherapy session date was defined as the index date, and the OS/ILCM was calculated from the index date to the date of death or until December 31, 2022 (the censoring date of the death Modified from SPACE 8 and CHISEL, 9 and the National Comprehensive Cancer Network NSCLC 2024v1 treatment guidelines. 4I G U R E 1 STROBE study flowchart and number of individuals at each stage of the study. 1 To ensure data consistency, only treated patients (class 1-2) and those with a single record were included. 2Without missing information regarding survival status in the TCR and death registry.
registry).The study flowchart, as suggested by the STROBE guidelines, 18 is shown in Figure 1.

Covariates
We collected related covariates based on recent relevant studies and our clinical research experiences [8][9][10]  in Taiwan was classified as north and non-north.SES was classified as an income equivalent to minimum wage or lower, or higher than minimum wage.Comorbidity was determined using the Charlson comorbidity index score and classified as ≥1 or <1 as per modifications from the literature. 19 was classified as yes or no.Eastern Cooperative Oncology Group (ECOG) performance status was scored as 0-1 or 2.

Statistical and supplementary analyses
[22][23][24] We used a logistic regression model with the abovementioned covariates to estimate PS. 24 After PSW, the standardized difference was used to assess the covariate balance between groups. 25,26We then compared the hazard ratio (HR) of death between the groups during the entire followup period.We analyzed all patients who initiated SABR (fractional dose ≥6 Gy) or CFRT (fractional dose within 2-2.5 Gy) regardless of the received biological dose to mimic the intention-to-treat (ITT) analyses.8][29][30] Regarding potential unmeasured confounders, we used the E-value to assess the robustness of our findings. 31,32The incidence of ILCM between groups was evaluated using a competing risk approach in the weighted sample. 33We used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM coding (5080/5081 and J700/J701, respectively 34 ) to estimate the occurrence of radiation pulmonary toxicity within 6 months of radiotherapy. 22n the supplementary analyses (SA), we conducted five additional analyses to evaluate the robustness of our findings.SA-1 was a per-protocol (PP) analyses including only those patients who received the intended dose (BED (10) ≥87.5 and fraction number ≤10 for SABR or BED (10) within 62.5-84 for CFRT) with the same analytic approach as in the primary analyses.SA-2 was an alternative analytic approach, including propensity score matching (PSM) 20,24 within the SA-1 study population to construct a 1:1 PS-matched cohort (without replacement).We compared the HR using a robust variance estimator 27 and adopted the sub-distribution HR to assess ILCM employing the clustered Fine-Gray model. 35e compared the rate of radiation pulmonary toxicity using McNemar's test. 36In SA-3, we limited the radiotherapy dose/ fractionation for the two groups (SABR [BED (10) ≥100 Gy] vs. CFRT [BED (10) within 72-84 Gy]) in the SA-1 study population to explore the difference between them when a more radical radiotherapy dose 6,8,37 was used.In SA-4, we limited the analysis to patients in the SA-1 study population potentially compatible with the national health insurance criteria for SABR (medically inoperable), according to TCR records.In SA-5, we considered urinary tract infection (UTI), modified from the literature 38 and not expected to be associated with thoracic radiotherapy, as the negative control outcome. 39UTI occurrence post thoracic radiotherapy was then compared within the SA-1 study population using methods suggested in the literature. 22tatistical analyses were performed using SAS software (version 9.4; SAS Institute) and R (version 4.3.0;R Development Core Team, R Foundation for Statistical Computing).

Study population
As shown in Figure 1, 351 eligible patients with clinical early-stage NSCLC who received either SABR (290 patients) or CFRT (61 patients) between 2011 and 2021 were included in the primary analysis.Patient characteristics are described in Table 2.All covariates were well balanced (standardized differences ≈ 0) after PSW with overlap weights, although some (sex, residency region, SES, tumor size, period, T stage, use of PET, use of systemic therapy, performance status) were imbalanced before PSW. 25  unadjusted analysis, the 5-year OS rates were 22% (CFRT group) and 45% (SABR group) (log-rank test, p = 0.044) (Figure 2).The PSW-adjusted OS curve is shown in Figure 3.The 5-year PSW-adjusted OS rates were 24% (CFRT group) and 46% (SABR group).When comparing the SABR and CFRT groups, the PSW-adjusted HR of death was 0.75 (95% CI 0.53-1.07,p = 0.118).This observed value could be explained by an unmeasured confounder associated with the selected treatment (CFRT or SABR) and survival with a risk ratio of 1.74 (E-value)-fold each.However, weaker confounding factors could not explain this association.Furthermore, the result for ILCM (HR = 0.68, p = 0.226) and the rate of radiation pulmonary toxicity after radiotherapy (<5%, p = 0.664) were not significantly different between the groups, but the details were not reported owing to HWDC data policy.

Supplementary analyses
In the SA-1 group, 270 and 53 patients in the SABR and CFRT groups received per-protocol radiotherapy doses, respectively.Patient characteristics are described in Table 3.
All covariates achieved a good balance after PSW with overlapping weights.When the SABR group was compared with the CFRT group, the PSW-adjusted HR of death was 0.88 (95% CI 0.60-1.30,p = 0.520).The PSW-adjusted OS curves are shown in Figure 4.The result for ILCM remained insignificant between the groups (HR = 0.69, p = 0.287).The rate of radiation pulmonary toxicity was similarly low (<5%) in both groups, but the details were not reported due to the HWDC data policy.
In SA-2, the constructed PS-matched subgroup (n = 98) with a good balance of covariates after PSM is presented in Table 4.The Kaplan-Meier OS curve is shown in Figure 5.The 5-year OS rates were 27% (CFRT group) and 40% (SABR group).Compared to CFRT, the OS (HR = 0.94, 95% CI 0.56-1.59,p = 0.829) and ILCM (HR = 0.71, p = 0.230) of patients receiving SABR had no significant difference between the groups.The rate of radiation pulmonary toxicity was similarly low (<5%) in both groups.The details were not reported due to the HWDC data policy.
Among the 303 patients in SA-3 (Table 5), the PSWadjusted HR of death was 0.94 (95% CI 0.63-1.38,p = 0.736) when the SABR group was compared to the CFRT group, as seen in Figure 6.ILCM results remained similar (HR = 0.76, p = 0.423).The rate of radiation pulmonary toxicity was similarly low (<5%) in both groups and the details were not reported.
Among the 77 patients in SA-4 (Table 6), PSWadjusted HR of death was 0.23 (95% CI 0.01-4.09,Tumor size (mm) p = 0.317) when the SABR group was compared to the CFRT group.The results for ILCM were similar (HR = 0.23, p = 0.148).The rate of radiation pulmonary toxicity was similarly low (<5%) in both groups and the details were not reported.
In SA-5, the occurrence of UTI after thoracic radiotherapy was similar in both groups (29% vs. 21% for SABR vs. CFRT, respectively), without any significant difference (PSW-adjusted odds ratio 1.58, p = 0.342), therefore no obvious unmeasured confounding biases were detected during the current analyses. 39

DISCUSSION
In this updated retrospective cohort study using the target trial emulation framework, we found that the OS of patients with unresected clinical early-stage NSCLC treated with SABR did not significantly differ from that of patients treated with CFRT after covariate adjustment in both the primary and supplementary analyses.However, a trend in favor of SABR was observed, which reached significance in the analyses without covariate adjustment.We searched PubMed using the phrase "target trial emulation NSCLC radiotherapy" on March 17, 2024 and found no relevant studies.Therefore, to the best of our knowledge, our study is the first to research this topic using a target trial emulation framework.
Our results were consistent with those of a systematic review published in 2023, 7 in that there was no significant difference between the efficacies of SABR and CFRT.No additional RCTs have been reported according to a review published in 2024 6 ; however, the preliminary results of a relevant ongoing RCT (LUSTRE) reported no significant difference in OS (HR of death 1.18, p = 0.4) 37 between SABR and hypofractionation at 60 Gy/15 Fx.In another RCT, this radiotherapy dose (60 Gy/15 Fx) has been reported to have a similar OS to that of CFRT with 60 Gy/30 Fx for locally advanced NSCLC. 40When compared with our earlier research, 10 this updated study had a similar conclusion, but with a larger sample size (n = 351) and an extended followup period >10 years.The crude 5-year OS (45%) for the SABR arm in our primary analysis may also be compatible with reports by two large institutions in Taiwan. 41,42Regarding other studies from Asia included in the above mentioned systematic review, 11 Karasawa et al. reported adjusted HR of 0.9143 (p = 0.69) for OS when accelerated hypofractionated radiotherapy was compared to SBRT, 43 whereas Tong et al did not report OS. 44However, given the non-randomized nature of this study, our results should be interpreted with caution and results from further studies, especially ongoing RCTs such as LUSTRE, are eagerly awaited.Until more convincing evidence becomes available, our findings can inform shared decision-making regarding radiotherapy regimens for early stage NSCLC not suitable for surgery, especially for ultra-central cases where SABR may carry a higher risk of complications. 45Considering this, CFRT or hypofractionation could be considered reasonable alternatives, as suggested in the 2024 European guidelines. 46Furthermore, for radiotherapy centers not able to perform SABR (such as 42% reported in United Kingdom 2019 survey 47 ), CFRT could also be a reasonable alternative.
Our study has several limitations.First, there are always possible unmeasured confounders in retrospective cohort studies like ours, such as tumor location (central vs. peripheral). 45There were also possible data accuracy issues in studies using secondary data.Although "TCR is one of the highest-quality cancer registries in the world," 14 it was still not perfect.Furthermore, the choice of treatment was based on actual clinical practice rather than randomization.All the above issues may lead to bias, therefore we utilized the E-value 32 to assess the robustness of our findings.Moreover, we used the negative control outcome method 39 and did not find any obvious unmeasured confounding bias in the current analyses.Second, the sample size of the current study was moderate, which may have led to a wider CI.Third, we did not investigate other potentially relevant endpoints, such as quality of life 48 and patient-reported outcomes, owing to limitations in data availability.

CONCLUSION
In this updated retrospective cohort study using a target trial emulation framework, we found that the OS of patients with early-stage NSCLC treated with SABR was not significantly different from that of patients treated with CFRT.The results of the relevant ongoing clinical trials are eagerly awaited.

ORCID
Chun-Ru Chien https://orcid.org/0000-0002-2365-7641 Histology was classified as adenocarcinoma or non-adenocarcinoma.The study period was set as 2011-2017 or 2018-2021 owing to changes in the AJCC clinical staging criteria since 2018.The clinical T stage was classified as T1 or T2.History of PET, systemic therapy, and smoking F I G U R E 2 Unadjusted Kaplan-Meier survival curve for SABR versus CFRT in the whole study population.CFRT, conventional fractionated radiotherapy; SABR, stereotactic ablative radiotherapy.F I G U R E 3 PSW-adjusted Kaplan-Meier survival curve for SABR versus CFRT in the whole study population.CFRT, conventional fractionated radiotherapy; PSW, propensity score weighting; SABR, stereotactic ablative radiotherapy.
After a median follow-up of 31 months (range = 1-132 months), 200 deaths were observed (157 and 43 patients in the SABR and CFRT groups, respectively).In the F I G U R E 4 PSW-adjusted Kaplan-Meier survival curve for SABR versus CFRT in the first supplementary analysis.CFRT, conventional fractionated radiotherapy; PSW, propensity score weighting; SABR, stereotactic ablative radiotherapy.
5 A B L E 1Abbreviations: AJCC, American Joint Committee on Cancer; BED, biologically effective dose5; CFRT, conventional fractionated radiotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; ILCM, incidence of lung cancer mortality; ITT, intention-to-treat; NSCLC, non-small-cell lung cancer; OS, overall survival; PP, per protocol; SABR, stereotactic ablative radiotherapy; TCR, Taiwan Cancer Registry.a Patient characteristics for the whole study population in the primary analysis.
Patient characteristics for the study population in the first supplementary analysis.
Patient characteristics for the study population in the second supplementary analysis.
Abbreviations: CFRT, conventional fractionated radiotherapy; PET, positron emission tomography; PSW, propensity score weighting; SABR, stereotactic ablative radiotherapy; SD, standard deviation.a Rounded.F I G U R E 5 Kaplan-Meier survival curve for SABR versus CFRT in the second supplementary analysis.CFRT, conventional fractionated radiotherapy; SABR, stereotactic ablative radiotherapy.T A B L E 5 Patient characteristics for the study population in the third supplementary analysis.SABR (n = 252) CFRT (n = 51) Standardized difference a Number or mean (SD) a T A B L E 6 Patient characteristics for the study population in the fourth supplementary analysis.
The exact numbers are not reported because of a Health and Welfare Data Science Center (HWDC) database center policy to avoid numbers ≤2 in single cells.
a Rounded.b